The proposed research is a continuation of our ongoing studies of the role of the bone morphogenetic proteins (BMPs) in lineage commitment by neural stem/progenitor cells (NPCs) in both the developing and the adult brain. In the adult hippocampus, exposure to exercise or environmental enrichment (hereafter: environmental exposure) attenuates levels of BMP signaling in association with increased neurogenesis and enhancement of cognitive performance. Infusion of the BMP inhibitor, noggin, into the ventricles of adult mice reproduces the effects of an environmental exposure on both neurogenesis and cognition. Similarly, transgenic inhibition of BMP signaling enhances both neurogenesis and cognition whereas transgenic overexpression of BMP4 inhibits neurogenesis and impairs cognitive performance. The effects of noggin infusion or overexpression are blocked by infusion into the ventricles of cytosine arabinoside (AraC), an inhibitor of cell proliferation. These findings lead to the hypothesis that BMP signaling is both necessary and sufficient to mediate changes in hippocampal neural niche properties and behavior in response to environmental exposure. We further hypothesize that coordinated neural activity during environmental exposure mediates effects on BMP signaling by membrane depolarization of progenitor cells (regulating BMP4) and granule cells (regulating noggin). This proposal will therefore test the general hypothesis that BMP signaling is a crucial link between the environment and both behavior and the cellular properties of the adult hippocampal neural niche. Specifically we will determine whether reduced BMP signaling is a requirement for the effects of environmental exposure on hippocampal neurogenesis and cognitive behavior, whether inducible cre-mediated ablation of BMP receptors from stem cells in the adult hippocampus alters neurogenesis or cognition, and whether the ablation of BMP receptors from adult NPCs blocks effects of the environment on hippocampal neurogenesis and behavior. A unique feature of these studies is the gain as well as loss of behavioral function that can be correlated with concurrent anatomic changes in the hippocampus. It is hoped that these studies will indicate biochemical loci where therapeutic intervention in disease processes may lead to a return to normal neurological function. More specifically, understanding the factors that maintain stem cell quiescence as well as the factors that promote neurogenesis in the adult brain may lead to therapies designed to facilitate repair of the damaged nervous system by endogenous stem cells present in the adult brain. PUBLIC HEALTH RELEVANCE: In the adult brain new cells are made continuously in the hippocampus, a part of the brain that is critical for memory and other cognitive functions. Exercise or exposure of an animal to an enriched environment increases the rate of production of new cells and enhances cognitive performance. The goal of these studies is to understand how the environment influences the production of new cells in the hippocampus and ultimately to develop therapeutic techniques for restoring function in cognitively impaired individuals.